Efficient synthesis of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones

ABSTRACT

A novel process and intermediates thereof for making 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones of the type shown below from appropriate phenyl hydrazines is described. 
     
       
         
         
             
             
         
       
     
     These compounds can be useful as factor Xa inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of and claims priority to applicationSer. No. 11/235,647, filed Sep. 26, 2005, now U.S. Pat. No. 7,304,157,which claims priority from U.S. provisional application No. 60/613,754filed Sep. 28, 2004, and U.S. provisional application No. 60/637,623filed Dec. 20, 2004, the contents of which are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates generally to processes for the preparationof 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones and intermediates for thesynthesis of the same, such pyrazolo-pyridinones can be useful as factorXa inhibitors.

BACKGROUND OF THE INVENTION

4,5-Dihydro-pyrazolo[3,4-c]pyrid-2-one compounds, like those describedin WO 03/26652, are currently being studied as factor Xa inhibitors inclinical settings. Clinical trials and NDA submissions requirepractical, large-scale synthesis of the active drug and intermediatesfor making the active drug. Consequently, it is desirable to find newsynthetic procedures for making 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a novel process for making4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones.

The present invention relates to novel intermediates for the synthesesof 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones.

These and other objects, which will become apparent during the followingdetailed description of processes relating to compounds of the followingformula.

DETAILED DESCRIPTION OF THE INVENTION

Thus, in a 1^(st) embodiment, the present invention provides a novelprocess for preparing a compound of formula IIIa:

comprising:

-   -   (a) contacting a compound of formula I with a compound of        formula II in the presence of a first base to form a compound of        formula III;

-   -   (b) contacting a compound of formula III with an R^(1b)-metal        reagent to form a compound of formula IIIa;        wherein:    -   Z is selected from Cl, Br, I, OSO₂CF₃, OSO₂Me, OSO₂Ph, and        OSO₂Ph-p-Me;    -   ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl,        and 4-methoxyphenyl;    -   R^(1a) is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, OCH₃, OCH₂CH₃,        OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃,        OCH₂CH(CH₃)₂, and OC(CH₃)₃;    -   R^(1b) is C₁₋₆ alkyl;    -   R is selected from Cl, Br, I, C₁₋₆ alkoxy, and NR¹R²;    -   R¹ and R² are independently selected from C₁₋₆ alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and        benzyl;    -   alternatively, NR¹R² is a 3-8 membered ring consisting of:        carbon atoms, N, and 0-1 O atoms;    -   ring A is substituted with 0-1 R⁴;    -   B is selected from F, Cl, Br, I, OSO₂CF₃, OSO₂Ph-p-Me, and        2-oxo-pyridyl; and    -   R⁴ is selected from H, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,        F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,        CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH(CH₃)₃, —CN, and CF₃.

In a 2^(nd) embodiment, the present invention provides a novel processwherein:

-   -   Z is selected from Cl, Br, and I;    -   ring D is selected from 3-chlorophenyl and 4-methoxyphenyl;    -   R^(1a) is selected from CH₃, CH₂CH₃, and CH₂CH₂CH₃;    -   R^(1b) is selected from CH₃ and CH₂CH₃;    -   R is selected from Cl, Br, I, and NR¹R²;    -   NR¹R² is selected from morpholino, pyrrolidino, and piperidino;    -   ring A is substituted with 0-1 R⁴; and    -   R⁴ is selected from H and F.

In a 3^(rd) embodiment, the present invention provides a novel processwherein:

-   -   Z is Cl;    -   ring D is 4-methoxyphenyl;    -   R^(1a) is CH₃;    -   R^(1b) is CH₃;    -   R is morpholino; and    -   ring A is unsubstituted.

In a 4^(th) embodiment, in reaction (a), the compound of formula I iscontacted with the compound of formula II followed by the addition ofthe first base.

In a 5^(th) embodiment, the first base in reaction (a) is a substitutedamine base.

In a 6^(th) embodiment, the substituted amine base is selected from:triethylamine, diisopropylethylamine, dabco, DBN, DBU, andN-methylmorpholine.

In a 7^(th) embodiment, the substituted amine base is triethylamine.

In a 8^(th) embodiment, in reaction (a), the contacting is performed inthe presence of a first aprotic solvent.

In a 9^(th) embodiment, the first aprotic solvent is ethyl acetate.

In a 10^(th) embodiment, reaction (a) further comprises contacting witha first strong acid.

In an 11^(th) embodiment, the first acid is HCl.

In a 12^(th) embodiment, the R^(1b)-metal reagent is a Grignard reagent.

In a 13^(th) embodiment, the Grignard reagent is CH₃MgCl.

In a 14^(th) embodiment, in reaction (b), the contacting is performed inthe presence of a second aprotic solvent.

In a 15^(th) embodiment, the second aprotic solvent is methylenechloride.

In a 16^(th) embodiment, the present invention provides a novel processfor preparing a compound of formula IIIb:

comprising:

-   -   (c) contacting the compound of formula IIIa with        2-hydroxy-pyridine in the presence of a catalyst, a        bidentate-diamine ligand, and a third aprotic solvent to form a        compound of formula IIIb; wherein:    -   ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl,        and 4-methoxyphenyl;    -   B is selected from F, Cl, Br, I, OSO₂CF₃, and OSO₂Ph-p-Me;    -   R^(1a) is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, OCH₃, OCH₂CH₃,        OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃,        OCH₂CH(CH₃)₂, and OC(CH₃)₃;    -   R^(1b) is C₁₋₆ alkyl;    -   ring A is substituted with 0-1 R⁴; and    -   R⁴ is selected from H, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,        F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,        CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH(CH₃)₃, —CN, and CF₃.

In a 17^(th) embodiment, the present invention provides a novel processwherein:

-   -   ring D is selected from 3-chlorophenyl and 4-methoxyphenyl;    -   B is I;    -   R^(1a) is selected from CH₃, CH₂CH₃, and CH₂CH₂CH₃;    -   R^(1b) is selected from CH₃ and CH₂CH₃;    -   ring A is substituted with 0-1 R⁴; and    -   R⁴ is selected from H and F.

In an 18^(th) embodiment, the present invention provides a novelprocess, wherein:

-   -   ring D is 4-methoxyphenyl;    -   B is I;    -   R^(1a) is CH₃;    -   R^(1b) is CH₃; and    -   ring A is unsubstituted.

In a 19^(th) embodiment, in reaction (c) the catalyst is a Cu(I) salt ora Pd(II) salt and the ligand is a phenanthroline.

In a 20^(th) embodiment, in reaction (c) the catalyst is selected fromCuI, CuCl, CuBr, and CuOTf.

In a 21^(st) embodiment, in reaction (c), the catalyst is CuI and theligand is 1,10-phenanthroline.

In a 22^(nd) embodiment, in reaction (c), the third aprotic solvent isselected from DMSO, toluene, N-methylpyrrolidinone, DMAC, and DMF.

In a 23^(nd) embodiment, in reaction (c), the third aprotic solvent isDMF.

In a 24^(th) embodiment, the present invention provides a novel processfor preparing a compound of formula IIIc:

comprising:

-   -   (d) contacting the compound of formula IIa with        2-hydroxy-pyridine in the presence of a catalyst and a fourth        aprotic solvent to form a compound of formula IIb;

-   -   (e) contacting a compound of formula I with a compound of        formula IIb in the presence of a second base to form a compound        of formula IIIc;

wherein:

-   -   Z is selected from Cl, Br, I, OSO₂CF₃, OSO₂Me, OSO₂Ph, and        OSO₂Ph-p-Me;    -   ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl,        and 4-methoxyphenyl;    -   R^(1a) is selected from NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,        CH₃, CH₂CH₃, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,        OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃, OCH₂CH(CH₃)₂, and OC(CH₃)₃;    -   R is selected from Cl, Br, I, C₁₋₆ alkoxy, and NR¹R²;    -   R¹ and R² are independently selected from C₁₋₆ alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and        benzyl;    -   alternatively, NR¹R² is a 3-8 membered ring consisting of:        carbon atoms, N, and 0-1 O atoms;    -   ring A is substituted with 0-1 R⁴;    -   B is selected from F, Cl, Br, I, OSO₂CF₃, and OSO₂Ph-p-Me; and    -   R⁴ is selected from H, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,        F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,        CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH(CH₃)₃, —CN, and CF₃.

In a 25^(th) embodiment, the present invention provides a novel processwherein:

-   -   Z is selected from Cl, Br, and I;    -   ring D is selected from 3-chlorophenyl and 4-methoxyphenyl;    -   R^(1a) is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, OCH₃, OCH₂CH₃,        OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃,        OCH₂CH(CH₃)₂, and OC(CH₃)₃;    -   R is selected from Cl, Br, I, C₁₋₆ and NR¹R²;    -   NR¹R² is selected from morpholino, pyrrolidino, and piperidino;    -   B is I;    -   ring A is substituted with 0-1 R⁴; and    -   R⁴ is selected from H and F.

In a 26^(th) embodiment, the present invention provides a novel processwherein:

-   -   Z is Cl;    -   ring D is selected from 3-chlorophenyl and 4-methoxyphenyl;    -   R^(1a) is selected from CH₃ and OCH₂CH₃;    -   R is selected from Cl and morpholino;    -   B is I; and    -   ring A is unsubstituted.

In a 27^(th) embodiment, in reaction (e), the compound of formula I iscontacted with the compound of formula IIb followed by the addition ofthe second base.

In a 28^(th) embodiment, the second base in reaction (e) is asubstituted amine base.

In a 29^(th) embodiment, the substituted amine base is selected from:triethylamine, diisopropylethylamine, dabco, DBN, DBU, andN-methylmorpholine.

In a 30^(th) embodiment, the substituted amine base isdiisopropylethylamine.

In a 31^(st) embodiment, in reaction (e), the contacting is performed inthe presence of a fifth aprotic solvent.

In a 32^(nd) embodiment, the fifth aprotic solvent is dichloroethane.

In a 33^(rd) embodiment, reaction (e) further comprises contacting witha second strong acid.

In a 34^(th) embodiment, the second acid is TFA.

In a 35^(th) embodiment, in reaction (d) the catalyst is a Cu(I) salt ora Pd(II) salt.

In a ₃₆ ^(th) embodiment, in reaction (d) the catalyst is selected fromCuI, CuCl, CuBr, and CuOTf.

In a 37^(th) embodiment, in reaction (d), the catalyst is CuI.

In a 38^(th) embodiment, in reaction (d), the fourth aprotic solvent isselected from DMSO, toluene, N-methylpyrrolidinone, DMAC, and DMF.

In a 39^(th) embodiment, in reaction (d), the fourth aprotic solvent isDMF.

In a 40^(th) embodiment, the present invention provides a novel processfor preparing a compound of formula IV:

comprising:

-   -   (f) contacting the compound of formula IIIc with a formamide in        the presence of a third base to form a compound of formula IV;        wherein:    -   the formamide is HC(O)NHR⁵;    -   the third base is an alkoxide;    -   ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl,        and 4-methoxyphenyl;    -   R^(1a) is selected from OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,        OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃, OCH₂CH(CH₃)₂, and OC(CH₃)₃;    -   ring A is substituted with 0-1 R⁴;    -   B is 2-oxo-pyridyl;    -   R⁴ is selected from H, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,        F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,        CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH(CH₃)₃, —CN, and CF₃; and    -   R⁵ is selected from H, CH₃, and CH₂CH₃.

In a 41^(st) embodiment, the present invention provides a novel processwherein:

-   -   ring D is selected from 3-chlorophenyl and 4-methoxyphenyl;    -   R^(1a) is OCH₂CH₃;    -   ring A is substituted with 0-1 R⁴;    -   R⁴ is selected from H and F; and    -   R⁵ is H.

In a 42^(nd) embodiment, the present invention provides a novel processwherein:

-   -   ring D is 3-chlorophenyl;    -   R^(1a) is OCH₂CH₃; and    -   ring A is unsubstituted.

In a 43^(rd) embodiment, in reaction (f), the formamide is HC(O)NH₂; andthe third base is a C₁₋₆ alkoxide and the counterion is selected fromLi, Na, K, Li, and Mg.

In a 44^(th) embodiment, in reaction (f), the third base is a sodiumC₁₋₂ alkoxide; and an alcoholic solvent corresponding to the alkoxide isalso present.

In a 45^(th) embodiment, in reaction (f), the third base is NaOMe andthe alcoholic solvent is methanol.

In a 46^(th) embodiment, reaction (f) is conducted in the presence of asixth aprotic solvent.

In a 47^(th) embodiment, the sixth aprotic solvent is selected fromDMSO, NMP, DMAC and DMF.

In a 48^(th) embodiment, the sixth aprotic solvent is DMF.

In a 49^(th) embodiment, the present invention provides a novel processfor preparing a compound of formula IIIb:

comprising:

-   -   (g) contacting a compound of formula III with an R^(1b)-metal        reagent to form a compound of formula IIIc;

wherein:

-   -   ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl,        and 4-methoxyphenyl;    -   R^(1a) is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, OCH₃, OCH₂CH₃,        OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃,        OCH₂CH(CH₃)₂, and OC(CH₃)₃;    -   R^(1b) is C₁₋₆ alkyl;    -   ring A is substituted with 0-1 R⁴;    -   R⁴ is selected from H, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,        F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,        CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH(CH₃)₃, —CN, and CF₃.

In a 50^(th) embodiment, the present invention provides a novel processwherein:

-   -   ring D is selected from 3-chlorophenyl and 4-methoxyphenyl;    -   R^(1a) is selected from CH₃, CH₂CH₃, and CH₂CH₂CH₃;    -   R^(1b) is selected from CH₃ and CH₂CH₃;    -   ring A is substituted with 0-1 R⁴; and    -   R⁴ is selected from H and F.

In a 51^(st) embodiment, the present invention provides a novel processwherein:

-   -   ring D is 4-methoxyphenyl;    -   R^(1a) is CH₃;    -   R^(1b) is CH₃; and    -   ring A is unsubstituted.

In a 52^(nd) embodiment, the R^(1b)-metal reagent is a Grignard reagent.

In a 53^(rd) embodiment, the Grignard reagent is CH₃MgCl.

In a 54^(th) embodiment, in reaction (b), the contacting is performed inthe presence of a seventh aprotic solvent.

In a 55^(th) embodiment, the seventh aprotic solvent is dichloromethane.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thus, theabove embodiments should not be considered limiting. Any and allembodiments of the present invention may be taken in conjunction withany other embodiment or embodiments to describe additional embodiments.Each individual element of the embodiments is its own independentembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment. In addition, the present invention encompassescombinations of different embodiment, parts of embodiments, definitions,descriptions, and examples of the invention noted herein.

Definitions

All examples provided in the definitions as well as in other portions ofthis application are not intended to be limiting, unless stated.

The present invention can be practiced on multigram scale, kilogramscale, multikilogram scale, or industrial scale. Multigram scale, asused herein, is can be in the scale wherein at least one startingmaterial is present in 10 grams or more, at least 50 grams or more, orat least 100 grams or more. Multikilogram scale means the scale whereinmore than one kilo of at least one starting material is used. Industrialscale means a scale which is other than a laboratory sale and which issufficient to supply product sufficient for either clinical tests ordistribution to consumers.

Equivalents mean molar equivalents unless otherwise specified.

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. Tautomers of compounds shown or described herein areconsidered to be part of the present invention.

“Substituted” means that any one or more hydrogens on the designatedatom is replaced with a selection from the indicated group, providedthat the designated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto(i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituentsare not present on aromatic moieties.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium. Isotopesof carbon include C-13 and C-14.

The present invention includes all stable oxides of thiol and aminogroups, even when not specifically written. When an amino group islisted as a substituent, the N-oxide derivative of the amino group isalso included as a substituent. When a thiol group is present, theS-oxide and S,S-dioxide derivatives are also included.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples ofalkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. C₁₋₆ alkoxy, includes C₁, C₂, C₃, C₄,C₅, and C₆ alkoxy groups. Examples of alkoxy include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, ands-pentoxy.

The reactions of the synthetic methods claimed herein may be carried outin the presence of a suitable base, said suitable base being any of avariety of bases, the presence of which in the reaction facilitates thesynthesis of the desired product. Suitable bases may be selected by oneof skill in the art of organic synthesis. Suitable bases includeinorganic bases such as alkyl lithium, hydrides, lithium amides, alkalimetal, alkali earth metal, thallium hydroxides, and ammonium hydroxides;alkoxides; phosphates; and, carbonates such as sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, cesiumcarbonate, thallium hydroxide, thallium carbonate, tetra-n-butylammoniumcarbonate, and ammonium hydroxide. Suitable bases include methyllithium, ethyl lithium, n-propyl lithium, i-propyl lithium, n-butyllithium, i-butyl lithium, s-butyl lithium, t-butyl lithium, hexyllithium, lithium bis(trimethylsilyl)amide, lithium diisopropylamide,lithium 2,2,2,-tetramethylpiperidine, potassiumbis(trimethylsilyl)amide, potassium hydride, or sodium hydride.

“Substituted amine base” includes a tertiary amine base. Examplesinclude trialkylamines wherein the three alkyl groups can be the same ordifferent. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. The alkyl groups onthe substituted amine base also include cycloakyl groups (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl) andcycloalkyl-alkyl groups (e.g., cyclopropyl-methyl, cyclobutyl-methyl,cyclopentyl-methyl, and cyclohexyl-methyl). Substituted amine bases canalso include monocyclic, bicyclic, and tryicyclic amine bases. Examplesof substituted amine bases include triimethylamine, triethylamine,tri-n-propylamine, diisopropylethylamine, dabco(1,4-diazabicyclo[2.2.2]octane), DBN (1,5-diazabicyclo[4.3.0]non-5-ene),and DBU (1,8-diazabicyclo[5.5.0]undec-7-ene).

“Strong base” or “strongly basic conditions” includes alkyl lithiums,lithium amides, hydride bases, other organometallic bases, andt-butoxides. Examples of strong bases include lithium tert-butoxide,sodium tert-butoxide, potassium tert-butoxide, methyl lithium, ethyllithium, n-propyl lithium, i-propyl lithium, n-butyl lithium, i-butyllithium, s-butyl lithium, t-butyl lithium, hexyl lithium, lithiumbis(trimethylsilyl)amide, lithium diisopropylamide, lithium2,2,2,-tetramethylpiperidine, potassium bis(trimethylsilyl)amide,potassium hydride, and sodium hydride.

“Strong acid” or “strongly acidic conditions” includes TFA(trifluoroacetic acid), sulfuric acid, and sulfonic acids (e.g., benzenesulfonic acid, toluene sulfonic acid, methyl sulfonic acid, andnaphthalene sulfonic acid).

Suitable aprotic solvents include ether solvents, tetrahydrofuran (THF),dimethylformamide (DMF), 1,2-dimethoxyethane (DME), diethoxymethane,dimethoxymethane, dimethylacetamide (DMAC), benzene, toluene,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare useful. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18^(th) ed., Mack Publishing Company, Easton,Pa., 1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Stable compound” and “stable structure” indicate a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

“Substituted” indicates that one or more hydrogens on the atom indicatedin the expression using “substituted” is replaced with a selection fromthe indicated group(s), provided that the indicated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound. When a substituent is keto (i.e., ═O) group, then 2 hydrogenson the atom are replaced.

Synthesis

By way of example and without limitation, the present invention may befurther understood by the following schemes and descriptions.

The 1,3-dipolar cycloaddition reaction of the present invention involvesreaction between the hydrazonoyl compound of formula I and dipolarophileof formula II. Compounds of formula I can be prepared as described in US2003/0181466, the contents of which are incorporated herein. Thiscycloaddition reaction provides the4,5-dihydro-pyrazolo[3,4-c]pyrid-2-one cores. The reaction can be run inthe presence of a substituted amine base (e.g., a non-nucleophilictertiary amine base). Examples of substituted amine bases include (a)trialkyamines (e.g., triethylamine and diisopropylethylamine) and cyclictertiary amines (e.g., N-methylmorpholine, dabco, DBN, or DBU), (b)trialkylamines and (c) triethylamine or diisopropylethylamine. Examplesof equivalents of base used include (a) about 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3,3.4, to 3.5 and (b) 3. Aprotic solvents (e.g., toluene, ethyl acetate,and dichloroethane) can be for the cycloaddition. The cycloaddition canbe run from room temperature up to the reflux point of the solvent.Examples of temperatures for the reaction include (a) from about 80, 85,90, 95, to 100° C. and (b) about 90° C.

Hydrazonoyl compound I can first be contacted with the base ordipolarophile (II), followed by addition of the second component. Forexample, dipolarophile (II) can be contacted with hydrazonoyl compund(I) and addition of the base can then follow. Alternatively, thehydrazone (I) can be contacted with a base and addition of dipolarophile(II) can then follow.

After contacting I and II in the presence of a base, the resultingproduct can be contacted with a strong acid. Examples of strong acidsinclude (a) TFA, sulfuric acid, nitric acid, and HCl and (b) TFA andHCl.

Alcohols IIIa and IIIb can be prepared from a compound of formula III(wherein R^(1a) can be a C₁₋₃ alkyl group and B can be I) or IIIb(wherein R^(1a) can be C₁₋₃ alkyl) via an alkyl-metal addition. Themetal reagent can be one of a variety of agents known to those of skillin the art (e.g., Grignard, Li, Zn, Mg, Ce, Ti, Al, Cd). Examples ofGrignard reagents include (a) MeMgBr, MeMgCl, MeMgCl, and Me₂Mg and (b)MeMgCl. Examples of solvents include (a) an aprotic, non-carbonylcontaining solvent, (b) THF, methyl-THF, toluene, MTBE, dichloromethane,and (c) dichloromethane. Examples of temperatures for the reactioninclude (a) about 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28,30, 32, 34, 36, 38, to 40° C. and (b) 10° C.

The compound of formula IIb/IIIb can be formed from formula IIa/IIIa bycontacting with 2-hydroxy-pyridine in the presence of a catalyst and anaprotic solvent. Examples of catalysts include (a) Cu(I) salt or aPd(II) salt, (b) CuI, CuCl, CuBr, CuOTf, and Pd(OAc)₂, and (c) CuI. Theaddition of 2-hydroxy-pyridine is generally aided by the presence of abase that is strong enough to deprotonate the hydroxyl group. Examplesof such bases include inorganic bases (e.g., phosphates (e.g., K₃PO₄),carbonates (e.g., K₂CO₃), hydroxides (e.g., KOH), and hydrides (e.g.,NaH)) and organic bases (e.g., NaHMDS, LDA, and t-butoxides (e.g.,KOtBu). An example of a base for IIIb is KOtBu. An example of a base forIIb is K₃PO₄. The formation of IIIb can be conducted in the presence ofbidentate-diamine ligands, which are known to those of ordinary skill inthe art (see, for example, Klapars et al, J. Am. Chem. Soc. 2002, 124,7421-28). Examples of ligands included, but are not limited to,phenanthrolines (e.g., 1,10 or 2,9), neocuproine, creatine, amino acids,8-hydroxy-quinoline, and 2-pyridamine and (b) 1,10-phenanthroline.Examples of the aprotic solvent include (a) a high boiling point solvent(e.g., boiling point over 60° C.), (b) DMSO, toluene,N-methylpyrrolidinone, DMAC, and DMF, and (c) DMF.

Amide IV can be formed from III (wherein R^(1a) is an ester (e.g., etherester) and B is 2-oxo-pyridyl) by contacting with a formamide and abase. Examples of formaides include (a) N-ethyl-formamide,N-methyl-formamide, or formamide and b) formamide itself. Examples ofbases include (a) alkoxides, (b) C₁₋₆ alkoxide, and (c) methoxide.Exampls of counterions for the alkoxide include (a) Li, Na, K, Li, andMg and (b) Na. The reaction can be conducted in the presence of analcohol that corresponds to the alkoxide base (e.g., C₁₋₆ alcohols andmethanol). Examples of solvents for the amidation include (a) aprotic,(b) DMSO, NMP, DMAC, and DMF, and (c) DMF. Examples of reactiontemperatures include (a) room temperature up to the reflux point of thesolvent used and (b) room temperature to 100° C.

Other features of the invention will become apparent in the course ofthe following descriptions of examplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

To acetic acid (102 g, 115, mL, 2.0 mol) was added water (120 g, 120 mL,6.66 mol), liquid HCl, 12.2M in H₂O (198 g, 165 mL, 2.01 mol), water(100 g, 100 mL, 5.55 mol), and then m-chloroaniline (128 g, 105 mL, 1.0mol) while maintaining the temperature at 20-30° C. This solution wasthen cooled to −5 to 0° C. and to it was added sodium nitrite (76.0 g,1.10 mol) and then water (150 g, 150 mL, 8.33 mol). To this solution wasadded sodium acetate trihydrate (272 g, 2.00 mol), followed by water(500 g, 500 mL, 27.8 mol). Toluene (218 g, 250 mL, 2.36 mol, ethyl2-chloro-3-oxo butanoic acid (165 g, 138 mL, 1.00 mol), and toluene(43.6 g, 50 mL, 473 mmol) were then sequentially added while maintainingthe temperature at −5 to 0° C. After maintaining the temperature at −5to 0° C. for 30 minutes, the solution was heated to 50-55° C. thereaction was complete and then cooled to 30-35° C. The organic (heavy)phase was removed. To the aqueous phase was added toluene (34.8 g, 40mL, 378 mmol) and heptane (246 g, 360 mL, 2.46 mol). This solution washeated to 40-55° C., and heptane (1.03 kg, 1.50 L, 10.2 mol) was addedover 1 hour. Once crystallization started, additional heptane was added(684 g, 1.00 L, 6.83 mol) over 1 hour. The solution was cooled to −5 to0° C. over two hours and held at this temperature for 2 hours. Theprecipitate was filtered and dried to provide the desired product (200g, 766 mmol, 0.766 equiv.).

To 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (100g, 260 mmol)(see Example 8 of US 2003/0181466), under a nitrogenatmosphere, were added 2-hydroxypyridine (37.1 g, 390 mmol), tribasicpotassium phosphate N-hydrate (82.8 g, 390 mmol), Cu(I) I (9.90 g, 52.0mmol), and DMF (535 g, 520 mL). While maintaining the nitrogenatmosphere, the solution was heated to 30-40° C. for about 15 minutesand then to 120-125° C. until the reaction was over 90% complete. Thesolution was cooled to about 30-40° C. and ammonium hydroxide 28 wt/wt %in water (156 g, 173 mL) was added. Water (347 g, 347 mL) was addedwhile maintaining the temperature at 20-30° C. Ammonium hydroxidesolution (10%) was added while the reaction mixture was at 30-40° C. Thesolution was cooled to 20-25° C. and agitated for about 1 hour. Theprecipitate was filtered and washed with water (520 g, 520 mL)(twice)and methyl t-butyl ether (742 g, 520 mL), and then dried to yield thedesired product (68.6-72.2 g, 0.195-0.205 mol, 0.75-0.79 equiv.).

To the products from Example 2 (50 g, 142.29 mmol, 1.00 equiv.) and fromExample 1 (74.30 g, 284.58 mmol, 2.00 equiv.) were added1,2-dichloroethane (499.20 g, 400 mL, 5.04 mol) anddiisopropylethylamine (55.17 g, 74.44 mL, 425.86 mmol). The reactionmixture was heated to 77° C. and stirred for 16 h to achieve a 90%conversion. After cooling to 40° C., TFA (64.90 g, 43.04 mL, 569.15mmol) was added dropwise, and the solution was heated to 80° C. for 1hour. After cooling to 25° C., water (400 g, 400 mL, 22.2 mol) was addedand the bottom phase collected. Ethanol (124.80, 100 mL, 1.26 mol) wasadded, and the solution was reduced by about 275 mL by distillation.After cooling to 5° C., ethanol (197.82 g, 250 mL, 4.29 mol) was added.Another 334 mL of the resulting solution were distilled off. Ethanol(197.82, 250 mL, 4.29 mol) was slowly added after cooling to 65° C. Thesolution was then cooled to 4° C. over 2 h. The resulting precipitatewas filtered, washed with acetone (395.05 g, 500 mL, 6.80 mol) and driedto yield the desired product (49 g, 70.4% yield).

Example 3 (1 kg, 2.05 mol, 1 equiv.) and DMF (9.45 kg, 10.0 L) werestirred at about 25° C. Formamide (2.26 kg, 2.0 L) was added and thesolution was heated to 50-55° C. over a period of about 10 min. Afterabout 10 min, 25 wt % sodium methoxide (0.4641 kg, 0.4937 L, 2.148 mol,1.05 equiv.) was added while the temperature was maintained at 50-55° C.After 15 minutes, 28 wt % ammonium hydroxide (2.56 kg, 2.85 L, 42.4 mol,20.7 equiv.) was added over 1 h. The reaction solution was cooled toabout 20° C. over about 1 h. The resulting precipitate was filtered,washed with water (10 kg, 10 L) (twice) and acetone (10 L) and dried.

P-anisidine (7.4 kg) was dissolved in water (18.6 l) and hydrochloricacid (33% HCl, 18 L) was added. The solution was heated to 40° C. andstirred for 30 minutes. The reaction mixture was then cooled to −5° C.,and an aqueous sodium nitrite (8 L at 40% w/w) solution was added.Afterwards, the reaction mixture was stirred for another 30 minutes atabout 0° C. The prepared solution was slowly dosed at −5° C. to asolution of aqueous sodium acetate (9.8 kg of NaOAc in 24 L of water),3-chloro-2,4-pentandione (8.17 kg), and acetone (18 L). The resultingmixture was stirred for 1 hour. The reaction mixture was then brought to25° C. over a 6 hour period. A slurry was formed. The precipitate wasfiltered and washed once with water. The isolated solid was dried undervacuum to obtain 12.2 kg of the desired product.

The products from Example 5 (4 kg, a second 3.9 kg batch was also run)and 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (4.5kg) were suspended in ethyl acetate (20 L), then triethylamine (2.45 l)was added. The transfer lines were rinse with 3.4 L of ethyl acetate.The resulting suspension was heated to 70° C. and stirred for about 4hours. Next, the solution was diluted with ethyl acetate (35 L) andwater (23.4 L). After cooling to 25° C., the solution was subjected to apolish-filtration to eliminate the fine particles. After phaseseparation, the aqueous phase was extracted with ethyl acetate (10.2 L).HCl (33% HCl, 2.35 L) was added to the combined organic layers, and themixture was heated to 5° C. for 90 minutes. After cooling to roomtemperature, water (20.5 L) was added. After phase separation, theorganic layer was extracted with sodium carbonate solution (34 L at 2.6w/w) and then water 34 L and 0.6 L of methanol. The resulting productsolution was reduced to 30% of the volume and petrol ether (47.5 L) wasadded. The rest of the ethyl acetate was removed by distillation.Methanol (9.5 L) was added, and the solution was brought to reflux forat about 10 minutes. While cooling, the product started to crystallize.The suspension was stirred for 1 hour at 20° C., and then the solidproduct was filtered off. The wet isolated product from the two batcheswere combined and dried to obtain 6.86 kg of desired product.

The product from Example 6 (2.5 kg, two batches of 2.5 kg were run) wasdissolved in methylene chloride (58 L) and reacted with a solution ofmethylmagnesium chloride in THF (3.45 kg, 3M) at 10° C. over 2 hours.The reaction was monitored by HPLC. Once the end-point was reached, thereaction mixture was transferred to another vessel with a 10 L rinse ofDCM (dichloromethane), and the reaction was quenched with an aqueoussolution of ammonium chloride (23.3 L, 12% w/w) at a temperature below20° C. After phase separation, the organic layer was washed withammonium chloride solution (23.3 L at 12% w/w) and then with water (236kg). Acetone (50 l) and toluene (23.6 l) was added, and a solvent swapwas performed by distilling off the methylene chloride. The resultingslurry was cooled to 5° C., and the product was filtered off and washedwith toluene (7.1 L) and heptane (7.1 L). The wet isolated product fromthe two batches were combined to obtain 3 kg of the desired product).

Under a nitrogen atmosphere, the product from Example 7 (3 kg), CuI(0.136 kg), 1,10-phenanthroline (0.214 kg), potassium tert-butoxide (1kg), and 2-hydroxypyridine (0.850 kg) were suspended in DMF (13.8 L).The DMF solvent was sparged with nitrogen before charging the reagentsto minimize the dissolved oxygen. The reaction mixture was heated to125° C. for 23 hours. The end-point was determined by HPLC. Once theend-point had been reached, the reaction mixture was cooled to about 25°C., and solid potassium phosphate (1.26 kg) powder was added. After 45minutes of stirring, ammonium hydroxide solution (15 l at 10% w/w) wasadded slowly and stirring was extended for 30 minutes while the productcrystallized out. The resulting slurry was then filtered and washedsuccessively with ammonium hydroxide (15 l, 10% w/w), water (three timeswith 15 l), and MTBE (15 l). The isolated final product was dried at50-60° C. under vacuum to obtain 2.12 kg.

A 5 L 3-neck round bottom flask was charged with Example 3 (100 g, 204mmol), DMF (800 mL), HCONH₂ (180 mL), and sodium methoxide (25 g, 252mmol). After the reaction mixture was stirred at 65° C. under N₂ for 1hour, aq. NH₄OH (800 mL 1N) was added over 30 minutes. The solid wascollected by filtration and washed with H₂O (3×500 mL). The white solidwas dried in vacuo at 50° C. for 16 hour to provide the product (91.0 g,96.8%) as white solid. ¹H NMR (DMSO): δ 7.79 (d, J=13.8 Hz, 2H); 7.63(d, J=7.2 Hz, 2H); 7.50 (m, 5H); 7.41 (d, J=8.2 Hz, 3H); 6.47 (d, J=9.3Hz, 1H); 6.30 (t, J=6.5 Hz, 1H); 4.10 (t, J=6.1 Hz, 2H); 3.22 (t, J=6.0Hz, 2H), 1.46 (t, J=7.1 Hz, 3H). ¹³C NMR (DMSO): δ 162.8, 161.0, 156.4,142.2, 141.5, 140.4, 140.2, 138.8, 138.2, 133.1, 132.4, 129.8, 128.1,126.8, 126.1, 125.9, 125.1, 124.0, 120.4, 105.5, 50.7, 20.9.

7-Oxo-6-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamidewas prepared similarly to Example 9.

7-Oxo-1,6-diphenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was prepared similarly to Example 9.

6-(4-Iodophenyl)-7-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamidewas prepared similarly to Example 9.

6-(4-Methoxyphenyl)-7-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamidewas prepared similarly to Example 9.

1-(3-Chlorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamidewas prepared similarly to Example 9.

1-(3-Chlorophenyl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamidewas prepared similarly to Example 9.

1-(3-Chlorophenyl)-6-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamidewas prepared similarly to Example 9.

To the products from Example 2 (10.00 g, 28.46 mmol, 1.00 equiv.) andfrom Example 5 (13.44 g, 42.69 mmol, 1.50 equiv.) were added1,2-dichloroethane (112.32 g, 90 mL, 1.14 mol) and diisopropylethylamine(5.52 g, 7.44 mL, 42.69 mmol). The reaction mixture was heated to 80°C., stirred for 24 h, cooled to 72° C., TFA (7.14 g, 4.73 mL, 62.61mmol) was added dropwise, and then the solution was stirred for 1 h.After cooling to 40° C., water (80.0 g, 80.0 mL, 4.44 mol) was added andthe bottom phase collected and washed with water (80.0 g, 80.0 mL, 4.44mol). Ethanol (126.61 g, 160 mL, 2.75 mol) was added, and the solutionwas reduced by about 90 mL by distillation. After cooling to 5o° C.,ethanol (63 g, 80 mL, 1.4 mol) was added. The solution was then cooledto room temperature. The resulting precipitate was filtered, washed withethanol (3×80 mL), and dried to yield the desired product (9.3 g, 72%yield).

The product from Example 17 (2.00 g, 4.40 mmol, 1.00 equiv.) wasdissolved in dichloromethane (79.50 g, 60.00 mL, 936.04 mmol), andcooled to 1.2° C. A solution of methylmagnesium chloride in THF (3M,2.22 g, 2.20 mL, 6.60 mmol) was then added, and the solution was allowedto warm to 5° C. After about 1.5 hours, additional methylmagnesiumchloride (0.25 mL) was added, and the solution was warmed to 8° C. Thereaction was quenched with an aqueous solution of ammonium chloride (30mL, 12% w/w), and the solution was allowed to rise to room temperature.After phase separation, to the organic layer was added ethanol (60 mL).About 100 mL of the solution was then distilled off. The solution wascooled to 65° C. and stirred for about an hour before cooling to roomtemperature. The resulting product was filtered off and washed withethanol (10 mL) and dried to give 1.63 g (78.8%) of the desiredproduct).

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

1. A process for preparing a compound of formula IIIc:

comprising: (d) contacting the compound of formula IIa with 2-hydroxy-pyridine in the presence of a catalyst and a fourth aprotic solvent to form a compound of formula IIb;

(e) contacting a compound of formula I with a compound of formula IIb in the presence of a second base to form a compound of formula IIIc;

wherein: Z is selected from Cl, Br, I, OSO₂CF₃, OSO₂Me, OSO₂Ph, and OSO₂Ph-p-Me; ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, and 4-methoxyphenyl; R^(1a) is selected from NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃, OCH₂CH(CH₃)₂, and OC(CH₃)₃; R is selected from Cl, Br, I, C₁₋₆ alkoxy, and NR¹R²; R¹ and R² are independently selected from C₁₋₆ alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl; alternatively, NR¹R² is a 3-8 membered ring consisting of: carbon atoms, N, and 0-1 O atoms; ring A is substituted with 0-1 R⁴; B is selected from F, Cl, Br, I, OSO₂CF₃, and OSO₂Ph-p-Me; and R⁴ is selected from H, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH(CH₃)₃, —CN, and CF₃.
 2. A process according to claim 1, wherein: Z is selected from Cl, Br, and I; ring D is selected from 3-chlorophenyl and 4-methoxyphenyl; R^(1a) is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, OCH(CH₃)CH₂CH₃, OCH₂CH(CH₃)₂, and OC(CH₃)₃; R is selected from Cl, Br, I, C₁₋₆ and NR¹R²; NR¹R² is selected from morpholino, pyrrolidino, and piperidino; B is I; ring A is substituted with 0-1 R⁴; and R⁴ is selected from H and F.
 3. A process according to claim 2, wherein: Z is Cl; ring D is selected from 3-chlorophenyl and 4-methoxyphenyl; R^(1a) is selected from CH₃ and OCH₂CH₃; R is selected from Cl and morpholino; B is I; and ring A is unsubstituted.
 4. A process according to claim 1, claim 2, or claim 3, wherein: in reaction (e), the compound of formula I is contacted with the compound of formula IIb followed by the addition of the second base.
 5. A process according to claim 1, claim 2, or claim 3, wherein: the second base in reaction (e) is a substituted amine base.
 6. A process according to claim 5, wherein: the substituted amine base is selected from: triethylamine, diisopropylethylamine, dabco, DBN, DBU, and N-methylmorpholine.
 7. A process according to claim 6, wherein: the substituted amine base is diisopropylethylamine.
 8. A process according to claim 1, claim 2, or claim 3, wherein: in reaction (e), the contacting is performed in the presence of a fifth aprotic solvent.
 9. A process according to claim 8, wherein: the fifth aprotic solvent is dichloroethane.
 10. A process according to claim 1, claim 2, or claim 3, wherein: reaction (e) further comprises contacting with a second strong acid.
 11. A process according to claim 10, wherein: the second acid is TFA.
 12. A process according to claim 1, claim 2, or claim 3, wherein reaction (d) the catalyst is a Cu(I) salt or a Pd(II) salt.
 13. A process according to claim 12, wherein: the catalyst is selected from CuI, CuCl, CuBr, and CuOTf.
 14. A process according to claim 13, wherein: the catalyst is CuI.
 15. A process according to claim 1, claim 2, or claim 3, wherein: in reaction (d), the fourth aprotic solvent is selected from DMSO, toluene, N-methylpyrrolidinone, DMAC, and DMF.
 16. A process according to claim 15, wherein: the fourth aprotic solvent is DMF. 